4-(diethylamino)-2-hydroxybenzaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N,N-diphenylhydrazine hydrochloride (79.5 g, 0.36 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) was slowly added to a solution of 4-diethylamino-2-hydroxybenzaldehyde (58.0 g, 0.3 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) in the presence of excess sodium carbonate. The reaction mixture was refluxed until all of the aldehyde reacted in about ½ hour. The residue obtained after evaporation of the solvent (800 ml) was treated with ether, and the ether extract was washed with water until the pH of the water reached 7. The organic layer was dried over anhydrous magnesium sulphate, treated with activated charcoal, and filtered. Then, the ether solvent was evaporated. The residue was recrystallized from ethanol. Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off and washed with cold ethanol. The yield was 85 g (78.8%). The melting point was found to be 95.5–96.5° C. (recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume). The 1H NMR spectrum (100 Mhz) of the product in CDCl3 was characterized by the following chemical shifts (in ppm): 11.55 (s, 1H, OH); 7.55–6.95 (m, 11H, CH═N, Ph); 6.7 (d, J=8.6 Hz; 1H, 6-H of 1,2,4-subst. Ph); 6.23 (s, 1H, 3-H of 1,2,4-subst. Ph); 6.1 (d, J=8.6 Hz, 1H, 5-H of 1,2,4-subst. Ph); 3.3 (q, J=8.0 Hz, 4H, CH2); 1.1 (t, J=8.0 Hz, 6H, CH3). An elemental analysis yielded the following results in weight percent: C, 76.68; H, 7.75; N, 11.45, which compared with calculated values for C23H25N3O in weight percent of: C, 76.85; H, 7.01; N, 11.69. reacted in about ½ hour The residue obtained after evaporation of the solvent (800 ml) was treated with ether the ether extract was washed with water until the pH of the water The organic layer was dried over anhydrous magnesium sulphate treated with activated charcoal filtered Then, the ether solvent was evaporated The residue was recrystallized from ethanol Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off washed with cold ethanol to be 95.5–96.5° C. recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume) An elemental analysis yielded the following results in weight percent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-(diethylamino)salicylaldehyde (10 g, 52 mmol, obtained from Aldrich) dissolved in 80 ml of 2-propanol, and N-methyl-N-phenylhydrazine (6.8 ml, 63 mmol, obtained from Aldrich) was added to a 250 ml round bottom flask equipped with a reflux condenser and a magnetic stirrer. The reaction mixture was refluxed until 4-(diethylamino)salicylaldehyde completely reacted. After the termination of the reaction, the reaction mixture was cooled to room temperature. The crystals formed were filtered and washed repeatedly with cold 2-propanol and dried under vacuum to yield 12.9 g (84%) of 4-(diethylamino)salicylaldehyde N-methyl-N-phenylhydrazone. The melting point was found to be 75.5–76.5° C. (recrystallized from 2-propanol). The 1H-NMR spectrum (100 Mhz) of the product in CDCl3 was characterized by the following chemical shifts (in ppm): 11.53 (s, 1H, OH); 7.63 (s, 1H, N═CH); 7.50–6.80 (m, 6H, Ar); 6.26 (m, 2H, Ar); 3.37 (m, 7H, CH2CH3, NCH3); 1.18 (t, 6H, CH2CH3, J=7.0 Hz). An elemental analysis yielded the following results in weight percent: C, 72.61; H, 7.88; N, 14.20, which compared with calculated values for C18H23N3O in weight percent of: C, 72.70; H, 7.80; N, 14.13. equipped with a reflux condenser and a magnetic stirrer completely reacted After the termination of the reaction The crystals formed were filtered washed repeatedly with cold 2-propanol dried under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N,N-diphenylhydrazine hydrochloride (79.5 g, 0.36 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) was slowly added to a solution of 4-diethylamino-2-hydroxybenzaldehyde (58.0 g, 0.3 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) in the presence of excess sodium carbonate. The reaction mixture was refluxed until 4-diethylamino-2-hydroxybenzaldehyde was completely reacted in about 30 minutes. The solvent (800 ml) was removed by evaporation. The residue obtained was extracted with ether and the ether extract was washed with water until the pH of the water reached 7. The organic layer was dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered. The ether solvent was evaporated. The residue was recrystallized from ethanol. Crystals were filtered off and washed with cold ethanol. The product was 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone. The yield was 85 g (78.8%). The melting point was found to be 95.5–96.5° C. (recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume). The 1H-NMR spectrum (100 Mhz) of the product in CDCl3 was characterized by the following chemical shifts (in ppm): 11.55 (s, 1H, OH); 7.55–6.95 (m, 11H, CH═N, Ph); 6.7 (d, J=8.6 Hz; 1H, 6-H of 1,2,4-subst. Ph); 6.23 (s, 1H, 3-H of 1,2,4-subst. Ph); 6.1 (d, J=8.6 Hz, 1H, 5-H of 1,2,4-subst. Ph); 3.3 (q, J=8.0 Hz, 4H, CH2); 1.1 (t, J=8.0 Hz, 6H, CH3). An elemental analysis yielded the following results in weight percent: C, 76.68; H, 7.75; N, 11.45, which compared with calculated values for C23H25N3O in weight percent of: C, 76.85; H, 7.01; N, 11.69. was completely reacted in about 30 minutes The solvent (800 ml) was removed by evaporation The residue obtained was extracted with ether the ether extract was washed with water until the pH of the water The organic layer was dried over anhydrous magnesium sulfate treated with activated charcoal filtered The ether solvent was evaporated The residue was recrystallized from ethanol Crystals were filtered off washed with cold ethanol to be 95.5–96.5° C. recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume) An elemental analysis yielded the following results in weight percent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N,N-diphenylhydrazine hydrochloride (79.5 g, 0.36 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) was slowly added to a solution of 4-diethylamino-2-hydroxybenzaldehyde (58.0 g, 0.3 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) in the presence of excess sodium carbonate. The reaction mixture was refluxed until all of the aldehyde reacted in about ½ hour. The residue obtained after evaporation of the solvent (800 ml) was treated with ether and the ether extract was washed with water until the pH of the water reached 7. The organic layer was dried over anhydrous magnesium sulphate, treated with activated charcoal, and filtered. Next, the ether solvent was evaporated. The residue was recrystallized from ethanol. Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off and washed with cold ethanol. The yield was 85 g (78.8%). The melting point was found to be 95.5-96.5° C. (recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume). The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 11.55 (s, 1H, OH); 7.55-6.95 (m, 11H, CH═N, Ph); 6.7 (d, J=8.6 Hz; 1H, 6-H of 1,2,4-subst. Ph); 6.23 (s, 1H, 3-H of 1,2,4-subst. Ph); 6.1 (d, J=8.6 Hz, 1H, 5-H of 1,2,4-subst. Ph); 3.3 (q, J=8.0 Hz, 4H, CH2); 1.1 (t, J=8.0 Hz, 6H, CH3). An elemental analysis yielded the following results in weight percent: C, 76.68; H, 7.75; N, 11.45, which compared with calculated values for C23H25N3O in weight percent of: C, 76.85; H, 7.01; N, 11.69. reacted in about ½ hour The residue obtained after evaporation of the solvent (800 ml) was treated with ether the ether extract was washed with water until the pH of the water The organic layer was dried over anhydrous magnesium sulphate treated with activated charcoal filtered Next, the ether solvent was evaporated The residue was recrystallized from ethanol Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off washed with cold ethanol to be 95.5-96.5° C. recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume) An elemental analysis yielded the following results in weight percent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N,N-diphenylhydrazine hydrochloride (79.5 g, 0.36 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) was slowly added to a solution of 4-diethylamino-2-hydroxybenzaldehyde (58.0 g, 0.3 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) in the presence of excess sodium carbonate. The reaction mixture was refluxed until all of the aldehyde reacted in about ½ hour. The residue obtained after evaporation of the solvent (800 ml) was treated with ether and the ether extract was washed with water until the pH of the water reached 7. The organic layer was dried over anhydrous magnesium sulphate, treated with activated charcoal, and filtered. Next, the ether solvent was evaporated. The residue was recrystallized from ethanol. Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off and washed with cold ethanol. The yield was 85 g (78.8%). The melting point was found to be 95.5-96.5° C. (recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume). The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 11.55 (s, 1H, OH); 7.55-6.95 (m, 11H, CH═N, Ph); 6.7 (d, J=8.6 Hz; 1H, 6-H of 1,2,4-subst. Ph); 6.23 (s, 1H, 3-H of 1,2,4-subst. Ph); 6.1 (d, J=8.6 Hz, 1H, 5-H of 1,2,4-subst. Ph); 3.3 (q, J=8.0 Hz, 4H, CH2); 1.1 (t, J=8.0 Hz, 6H, CH3). An elemental analysis yielded the following results in weight percent: C, 76.68; H, 7.75; N, 11.45, which compared with calculated values for C23H25N3O in weight percent of: C, 76.85; H, 7.01; N, 11.69. reacted in about ½ hour The residue obtained after evaporation of the solvent (800 ml) was treated with ether the ether extract was washed with water until the pH of the water The organic layer was dried over anhydrous magnesium sulphate treated with activated charcoal filtered Next, the ether solvent was evaporated The residue was recrystallized from ethanol Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off washed with cold ethanol to be 95.5-96.5° C. recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume) An elemental analysis yielded the following results in weight percent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 mL three necked, round bottom flask equipped with a mechanical stirrer, reflux condenser, and Y-tube with a rubber septum and nitrogen inlet was added 1.8 gm (45 mmol) of 60% sodium hydride in mineral oil. After washing twice with 20 mL of hexanes, 150 mL of THF was added, followed by the rapid dropwise addition via transfer syringe of 3.86 gm (20 mmol) of 4-(N,N-diethylamino)-2-hydroxy benzaldehyde, dissolved in 50 mL of tetrahydrofuran (THF). The flask was placed in an 80° C. oil bath and stirred vigorously for 5 minutes, at which time 2.08 mL (20 mmol) of methyl bromoacetate was added in one portion. Sodium bromide precipitated from solution and vigorous stirring had to be maintained throughout. The suspension was refluxed for 80 minutes, allowed to cool to room temperature, and diluted with 75 mL of diethyl ether. The reaction was quenched by the slow dropwise addition of 50 mL of dilute aqueous ammonium chloride. The phases were separated and the aqueous phase extracted with 100 mL of diethyl ether (Et2O). The combined organic phases were washed with 20 mL 1 N NaOH and 20 mL water. After drying (MgSO4), the solvent was removed by rotary evaporation and the residual oil purified by flash chromatography (CH2Cl2 ; SiO2, 11/2×15") to yield 2.23 gm (45.3%) of the product as a colorless oil. Field desorption mass spectrum: m/e 247 (M+). Anal. Calcd. for C14H17NO3C,: 68.0; H, 6.9; N, 5.7. Found: C, 67.9; H, 6.8., N, 5.8. 1H 270 NMR (CDCl3): δ6.7 (m, 2H, ArHa,b), 7.4 (m, 2H, ArHc,d). reflux condenser After washing twice with 20 mL of hexanes, 150 mL of THF was added was placed in an 80° C. was added in one portion Sodium bromide precipitated from solution to be maintained throughout The suspension was refluxed for 80 minutes diluted with 75 mL of diethyl ether The reaction was quenched by the slow dropwise addition of 50 mL of dilute aqueous ammonium chloride The phases were separated the aqueous phase extracted with 100 mL of diethyl ether (Et2O) The combined organic phases were washed with 20 mL 1 N NaOH and 20 mL water After drying (MgSO4) the solvent was removed by rotary evaporation the residual oil purified by flash chromatography (CH2Cl2 ; SiO2, 11/2×15")

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 90 mL of acetonitrile was dissolved 2.8 g (14.6 mmol) of 4-diethylaminosalicylaldehyde. To this solution were added 14.3 g (43.8 mmol) of cesium carbonate and 2.8 g (15.3 mmol) of 1-(2-chloroethyl)piperidine hydrochloride at room temperature and the mixture was stirred at 80° C. for 4 hours. Water (150 mL) was added to the resulting reaction mixture and extraction with ethyl acetate (100 mL×3) was performed. The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to quantitatively give 4.5 g of the title compound. The combined organic layer was dried over anhydrous sodium sulfate After filtration the solvent was evaporated under reduced pressure to quantitatively give 4.5 g of the title compound

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 90 mL of acetonitrile was dissolved 2.8 g (14.6 mmol) of 4-diethylaminosalicylaldehyde. To this solution were added 14.3 g (43.8 mmol) of cesium carbonate and 2.8 g (15.3 mmol) of 1-(2-chloroethyl)piperidine hydrochloride at room temperature and the mixture was stirred at 80° C. for 4 hours. Water (150 mL) was added to the resulting reaction mixture and extraction with ethyl acetate (100 mL×3) was performed. The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to quantitatively give 4.5 g of the title compound. The combined organic layer was dried over anhydrous sodium sulfate After filtration the solvent was evaporated under reduced pressure to quantitatively give 4.5 g of the title compound

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol), pyridine (0.19 mL, 2.3 mmol) in 1.6 mL of dry dichloromethane was added benzoyl chloride (216 μL, 1.84 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The mixture was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound as a white solid (432 mg, 94%). The mixture was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine dried over MgSO4 After filtration the filtrate was concentrated in vacuo the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol), pyridine (0.19 mL, 2.3 mmol) in 1.6 mL of dry dichloromethane was added benzoyl chloride (216 μL, 1.84 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The mixture was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound as a white solid (432 mg, 94%). The mixture was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine dried over MgSO4 After filtration the filtrate was concentrated in vacuo the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20)